131 Clinical relevance of P-glycoprotein-related resistance in patients with acute leukemia

Abstract

P-glycoprotein (P-gp) is a crucial factor in the development of chemotherapy resistance in malignant disorders. Between 1989 and 1994 P-gp expression was prospectively studied in mononuclear bone marrow cells of 304 (221 acute myelogenous leukemia, AML; 83 acute lymphoblastic leukemia, ALL) patients. In 282 patients P-gp was investigated before and after therapy and in 22 patients only before therapy: 148 AML patients with the AML-6 protocol (European Organization for Research on Treatment of Cancer), containing daunorubicin, vincristine and conventional-dose cytarabine (ara-C); and 63 AML patients were treated with intermediate-dose ara-C plus amsacrine. A further 71 ALL patients were treated according to a German standard polychemotherapy protocol (Bundesgesundheitsministerium fur Forschung and Technologie, BMFT04/1989). P-gp was determined by using monoclonal antibodies C219 and 4E3, and the cut-off point for P-gp overexpression was set at ≥10%. A significant (p<0.05) difference in P-gp overexpression was demonstrated between AML (21.7%) and ALL (10.2%) patients at primary diagnosis and between primary diagnosis and relapse/refractoriness in AML (21.7%; 51.2%) and ALL (10.2%; 27.2%) patients. According to French-American-British (FAB) classification, P-gp overexpression was detected in AML patients significantly (P<0.05) more frequently in classes M4, M5a, and M5b and less frequently in M3, as compared to other types. Of AML patients 35%, after therapy according to the AML-6 protocol, and 11.5%, after intermediate-dose ara-C plus amsacrine, as well as 7% of ALL patients after treatment developed P-gp overexpression. For AML patients with P-gp overexpression at primary diagnosis or early relapse/refractoriness, the predictive values for nonresponse to AML-6 protocol were 90% and 94%, respectively, while late-relapsed AML patients with P-gp overexpression had a significantly (p<0.05) lower predictive value of 73% for nonresponse. Additionally, in refractory and late-relapsed Pgp-overexpressing AML patients treated with intermediate-dose ara-C plus amsacrine, the predictive values for nonresponse were 44% and 39%, respectively, significantly (p<0.05) lower as compared to AML-6 protocol-treated refractory or late-relapsed AML patients. In P-gpoverexpressing treated ALL patients the predictive values of 50% and 55% for nonresponse were calculated at primary diagnosis and late relapse, respectively. We conclude that P-gp overexpression is a common phenomenon in AML patients at primary diagnosis or relapse, has an inverse influence on AML-6 treatment outcome, and should be taken into consideration in the development of new therapy strategies.